Poxiviruses are large DNA viruses that replicate in the cytoplasm of infected cells. Efforts are being made to determine the structure and mode of replication of poxvirus DNA which in some respects resembles the eukaryotic chromosome. Vaccinia virus, the prototype for this group, has a 180,000 base pair (bp) linear double-stranded DNA genome with covalently linked ends and a 10,000 bp inverted terminal repetition. Nucleotide sequence analysis revealed that the ends of the genome consist of hairpin loops so that the two DNA strands form one continuous polynucleotide chain. The 104 nucleotide apex of the loop is A T rich, incompletely base-paired and exists in two isomeric forms that are inverted and complementary in sequence (flip-flopped). The terminal loop is followed by several sets of tandemly repeating sequences. Models for the replication of the terminal segment of the poxvirus genome that involves site-specific nicking and lead to flip-flop rearrangements and head to head dimerization have been proposed. Genetic evidence that vaccinia virus encodes its own DNA polymerase has been obtained.